Synthesis of disubstituted pyridines

ABSTRACT

BY INTRODUCING AN ALKYL OR ARYL GROUP INTO THE 2-POSITION OF A 4-ALKYL OR 4-ARYL PYRIDINE WITH AN ALKYL OR ARYL LITHIUM REAGENT 2,4-ALKYL AND ARYL PYRIDINE COMPOUNDS CAN BE CONVENIENTLY PREPARED.

United States Patent Oflice 3,591,592 SYNTHESIS OF DISUBSTITUTED PYRIDINES Paul S. Anderson, North Wales, Pa., assignor to Merck & (10., Inc., Rahway, N J. No Drawing. Filed Mar. 29, 1963, Ser. No. 717,407 Int. Cl. C07d 31/20 US. Cl. 260-290 3 Claims ABSTRACT OF THE DISCLOSURE By introducing an alkyl or aryl group into the 2-position of a 4-alkyl or 4-aryl pyridine with an alkyl or aryl lithium reagent 2,4-alkyl and aryl pyridine compounds can be conveniently prepared.

SUMMARY OF THE INVENTION This invention relates to alkyl and aryl pyridine compounds and processes of alkylation and arylation for preparing them. The compounds included in this invention have proved to be effective starting materials for the synthesis of a number of important compounds as well as being commercially useful because of their basic properties.

BACKGROUND OF THE INVENTION Much difliculty has been encountered in the availability of 2,4-disubstituted pyridines. The costs resulting from their unavailability has limited their uses in organic chemistry.

Previous methods of preparing 2,4-disubstituted pyridines are generally reviewed in The Chemistry of Heterocyclic Compounds, Pyridine and Its Derivatives, Part Two, Chap. V, Alkylpyridine and Arylpyridines by Leon E. Tenenbaum, p. 155 forward (Interscience, 1961). Besides the conventional methods described, it is well known from the art how to introduce alkyl or aryl substituents at the 2-position of a pyridine molecule by reacting the pyridine with alkyl or aryl lithium compounds. It is further well known from the art how to introduce alkyl or aryl substituents at the 2-position of a 3-alkyl pyridine compound by reacting the 3-alkyl pyridine with an alkyl or aryl lithium compound. The reasons given for the reaction taking place at the 2-position is that the hydrogens on the 3-alkyl group are not acidic enough to react with the lithium reagent.

It is further well known from the art, however, that a 4-alkyl pyridine upon reacting with an alkyl or aryl lithium reagent in ether forms a lithium derivative of the 4-a1kyl pyridine as reported by Carl Osuch and Robert Levine, Journal of Organic Chemistry, volume 22, p. 939

There are usually many side reactions resulting when conventional methods are employed and the above reactions are carried out in an ether solvent [Henry Gilman and H. Smith Broadbent, J.A.C.S.: 70, p. 2809 (1948)]. This is due primarily because of the unpredictability of the complicated synthetic methods involved. The resulting side reactions increase the possibility of isomers present and decrease yields of desired product, for isomers are most often very diflicult to separate without extraordinary techniques. The unavailability of high quality reagents on a commercial scale and lack of sophistication in technique of handling reactive metallic organic reagents has been a drawback until recently. It is apparent that because of the variety of difiiculties that are present, synthesis of 2,4-disubstituted pyridines has been not only time consuming but economically unfeasible.

Patented July 6, 1971 DESCRIPTION AND PREFERRED EMBODIMENTS This invention more particularly relates to a method for preparing 2,4-disubstituted pyridines having the formula structure:

alkyl (preferably lower alkyl such as methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, etc., provided it is capable of forming an alkyl lithium reagent);

aryl (preferably phenyl or a substituted phenyl that is capable of forming an aryl lithium reagent) or aralkyl (preferably arlower alkyl such as benzyl, phenethyl, etc.); R is alkyl (preferably lower alkyl such as methyl, ethyl, propyl,

i-propyl, butyl, s-buty-l, i-butyl, t-butyl, etc.);

aryl (preferably phenyl) or substituted aryl (preferably substituted phenyl such as alkoxyphenyl (preferably lower alkoxyphenyl such as methoxyphenyl, etc.) or alkylphenyl (preferably lower alkylphenyl such as tolyl, xylyl, etc.), etc., provided the substituent will not react with the lithium reagent).

It further relates more particularly to a method for preparing 2,4-disubstituted pyridines that is both economical and noncomplicated. This invention still further relates to a method for obtaining 2,4-disubstituted pyridines in a high percentage yield from readily available starting materials. It again also relates to a synthesis of 2,4-disubstituted pyridines which does not result in complex mixtures of isomeric products that are diflicult to separate by ordinary means. What the present invention further relates to will become apparent to those skilled in the art by reading the specification.

The more preferred aspect of this invention relates to a method of synthesizing 2,4-diloweralkyl, 2-loweralkyl- 4-phenyl, 2-phenyl-4-loweralkyl-2,4-diphenyl, 2-arl0weralkyl-4-loweralkyl and 2-arloweral kyl-4-phenylpyridines.

As a result of the unavailability of 2,4-disubstituted pyridines and the costs resulting from their complicated isolation or synthesis, processes for the preparation of compounds which would incorporate 2,4-disubstituted pyridines as intermediates have been restricted. The ability to conveniently and economically synthesize 2,4-disubstituted pyridines of this invention also provides the utility for their use. They can now be economically employed as starting materials from which a number of important medicinal compounds can be synthesized in the antitubercular (Der. 25, 968) field. They further provide improved and economically feasible methods of preparing compounds used in herbicidal manufacture (Der. 9768), fumigants (C.A. 42:7912g) and copolymers (U.S. 2,826,569). They are stronger bases than pyridine and as a result they have many uses in commercial industry as salts for both organic and inorganic acids and for biologically active acids. They are also useful as solvents for reaction systems requiring a basic medium but requiring a solvent with a higher temperature than pyridine. They can be used as azeotropes and for chemical purification and separations.

I have found that an alkyl, aryl or aralkyl radical can be introduced into the 2-position of a 4-alkyl or 4-aryl pyridine. This can be accomplished by reacting the 4-alkyl or 4-aryl pyridine starting material with an alkyl, aryl or aralkyl lithium reagent under certain reaction conditions. Although any 4-alkyl or 4-aryl pyridine can be used as a starting material in this invention, it is preferable 4i particularly ether solvents (such as ethyl ether) and the like should be avoided.

The 4-alkyl and 4-aryl pyridines used in this invention are usually liquids and thus can be added dropwise to to use a 4-lower alkyl pyridine such as 4-methyl, 4-ethyl, 5 the lithium reagent solution. It is preferable to dissolve 4-propyl, 4-i-propyl, 4-butyl, 4-s-butyl, 4-i-butyl, 4-t-butyl, the 4-alkyl or 4-aryl pyridine in an inert hydrocarbon etc. pyridine or 4-phenyl or 4-substituted phenyl pyridine. solvent (such as benzene, toluene, hexane, pentane, pe- The 4-substituted pyridines used should not have substitutroleum ether, and the like). Usually the same type solvent ents that will react themselves with the lithium reagent, is used as that inert solvent in which the lithium reagent such as halophenyl. The preferable alkyl, aryl or aralkyl is dissolved to render it inactive. This is not absolutely lithium reagents used are alkyl, aryl or aralkyl lithium necessary, however. The solvents used should be free from reagents wherein the alkyl group is a lower alkyl such moisture and this can be accomplished by use of suitable as methyl lithium reagent, ethyl lithium reagent, propyl drying agents such as molecular sieves. It is preferable lithium reagent, i-propyl lithium reagent, butyl lithium that the reaction be carried out in a dry, inert atmosphere. reagent, i-butyl lithium reagent, s-butyl lithium reagent, It has further been found that in order to insure propt-butyl lithium reagent, etc. The preferable aryl group erly substituted end products in high yields there should is phenyl such as phenyl lithium reagent or any substibe a 1:1 molar ratio of the 4-alkyl or 4-aryl pyridine and tuted phenyl group that is capable of forming a phenyl the alkyl or aryl lithium reagent. If a 1:1 molar ratio of lithium reagent that will react in this process as does the the starting materials is not used, there may be additional phenyl lithium reagent (preferably p-methoxyphenyl 2O substitution at the 6-position of the pyridine compound. lithium reagent, etc.). The preferable aralkyl group is The desired 2,4-disubstituted pyridines of the present arloweralkyl such as benzyl lithium reagent or phenethyl invention can be isolated from the reaction mixture by lithium reagent. methods well known in the art. One preferable method The various starting materials of this invention includ- P is hydrolysis of the reaetioh mixture in ing the lithium reagents and the 4-substituted pyridines an lee'water'mlhthre followed hY extrachfm of the P are known throughout the literature and many are ucts from this mixture with an inert organic solvent (such cerciany avai1ah1e as diethyl ether) and the concentration of the organic In order to obtain the desired products of this invention, solYeht to e A salt can then h lsolated from h it has been f d that the 1 or 4 ary1 pyridine; must residue which can then be recrystallized toetfect purity be added to a solution of the lithium reagent. The addie the f h t can be Punfied from the residue by free tion of the 4-alkyl or 4-aryl pyridine to the lithium reagent hohal dlshhahom solution should be performed at a slow rate and prefh fohollflhg are detalled examhles of h Processes erably dropwise. The reagents should n be mixed of this nvent on. They are to be considered as illustrations gether simultaneously. At an increased addition speed the of the lhvehhoh and are hot hmltahohs thereofdesired products will not be produced. Once the 4-alkyl EXAMPLE 1 or 4-aryl pyridine is added to the lithium reagent, the mixture should be heated to a temperature of about 70 2'ethyl4'methyl'pyndme 100 C. for a period of time that is sufficient to complete To a stirred solution of 1 mole of ethyl lithium in the reaction. This time may vary from 5-10 hours. The 500 ml. of benzene is added dropwise with stirring 1 reaction is usually run at a temperature which is the mole (93 grams) of 4-methylpyridine. After the addition reflux temperature of the particular hydrocarbon solvent is complete, the reaction mixture is heated under refiuX in which the lithium reagent is dissolved. In order '[0 for eight hours, cooled and poured onto ice, The reacobtain the maximum yields of the desired product, hoW- tion mixture is stirred and then the organic layer is ever, it is Preferable that the reaction between the y separated and extracted with aqueous hydrochloric acid or 4-aryl pyridine and the lithium reagent be carried out (25%). The acid extracts are combined, made basic at about 80 C. for at least 5 hours. with concentrated aqueous ammonia and extracted with The lithium reagents used as starting materials in this ether. The combined ether extracts are dried over maginvention are usually sold commercially and are dissolved nesium sulfate, filtered and evaporated to yield a liquid in an inert hydrocarbon solvent (such as benzene, toluene, which is then distilled and on redistillation gives 77 g. of hexane, pentane, petroleum ether, and the like). If the 2-ethyl-4-methylpyridine, B.P. 107l08/85 mrn. lithium reagent is prepared it is prepared in an ether solvent and then the ether is replaced with a hydrocarbon EXAMPLE 2 solvent and should preferably be done so before the When the procedure of Example 1 is followed but sub 4-alkyl or 4-aryl pyridine is added to it. The use of a stituting the reagents listed in Table I below for the hydrocarbon solvent is a preferred aspect of this invenreagents of Example 1, there is obtained the correspondtion. Solvents which promote alkylation at the 4-position, ing 2,4-disubstituted pyridines.

TABLE I Starting pyridine Lithium reagent Solvent Product 4-inethylpyridine Do 4-ethylpyridino 4-propylpyridine.

4-methyl-2-propylpyridine. 4-methyl-2-i-propyl pyridine. 4-ethyl-Z-propylpyridine. 2,4-dipr0pylpyridine.

entane 4-methylpyridine n-Butyl lithium. 4methyl-2-butylpyridine.

Do Scc-butyllithium Heptane 4-niethyl-2-scc-butylpyridine. Do t-Butyl lithium 1: 1 toluene/benzene 4-mothyl-2-t-butylpyridino. 7:3 benzene/ether 4methyl-Z-phenylpyrldine.

4-cthylpyridine 4-methylpyridine 4phenylpyridine Phenethyl lithium" Ethyl lithium do 4-ethyl-2-phenylpyridine. 4-methyl-2-phenethylpyridino.

4phenyl-2-ethylpyridine.

Do. n-Propyl lithium 5: 1 toluene/ethen 4-phenyl-2-propylpyridine. Do Phenyl lithium 7:3 benzene/ether. 2,4-dlphenylpyridine. Do Benzyl lithium Benzene 4-phcnyl-2-benzylpyridine. p-Metho phenyl Ethyl lithium -do 4-(p-methoxyphenyl)-2-ethylpyridine. pyridine.

1 The pentane is removed and replaced with the higher boiling mixture of 1:1 toluene-benzene after addition of the 4-methylpyridiiic.

I claim: 1. A process for the preparation of 2,4-disubstituted pyridine of the formula:

wherein R is as described above, dropwise to an organo lithium reagent of the formula RLi wherein R is as described above in an inert hydrocarbon solvent selected from the group consisting of benzene, toluene, hexane, pentane and petroleum ether at a temperature of C.- l00 C. wherein the 4-substituted pyridine and the organo lithium reagent are in a 1:1 mole ratio.

2. A process according to claim 1 wherein R and R are both lower alkyl.

3. A process according to claim 1 wherein R is ethyl and R is methyl.

References Cited Osuch, J. Org. Chem., v01. 22, pp. 639-943 (1957).

JOHN D. RANDOLPH, Primary Examiner H. I. MOATZ, Assistant Examiner US. Cl. X.R. 260-297R 

